The macrosialin promoter directs high levels of transcriptional activity in macrophages dependent on combinatorial interactions between PU.1 and c-Jun.
Macrosialin is a transmembrane glycoprotein that is highly expressed in macrophages. In the present studies, macrosialin mRNA levels are shown to be markedly up-regulated during macrophage differentiation of bone marrow progenitor cells in response to macrophage colony-stimulating factor and granulocyte-macrophage colony-stimulating factor. To investigate the mechanisms responsible for regulation of macrosialin expression, we have isolated the macrosialin gene and performed an initial analysis of its transcriptional regulatory elements. The macrosialin promoter and 7.0 kilobase pairs of 5'-flanking information direct high levels of reporter gene activity in monocyte/macrophage-like cells, but little or no expression in nonmyeloid cells. This pattern of expression is dependent on regulatory elements located between -7.0 and -2.5 kilobase pairs from the transcriptional start site that exhibit strong enhancer activity in macrophages and repressor activity in nonmyeloid cells. Analysis of the proximal macrosialin promoter indicates that combinatorial interactions between at least four classes of transcriptional activators, including PU.1/Spi-1 and members of the AP-1 family are required for basal promoter function. PU.1/Spi-1 and c-Jun act synergistically to activate the macrosialin promoter in a nonmyeloid cell line, suggesting that combinatorial interactions between these proteins are involved in regulating macrosialin expression during macrophage differentiation.
Li
A C
AC
Division of Cardiology, Department of Medicine, University of California, San Diego, La Jolla, California 92093-0651, USA.
Guidez
F R
FR
Collier
J G
JG
Glass
C K
CK
D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D001483:Base Sequence; D002454:Cell Differentiation; D003001:Cloning, Molecular; D004742:Enhancer Elements, Genetic; D018507:Gene Expression Regulation, Developmental; D017930:Genes, Reporter; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D012045:Regulatory Sequences, Nucleic Acid; D017422:Sequence Analysis, DNA; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D000099232:Proto-Oncogene Protein Spi-1; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D016173:Macrophage Colony-Stimulating Factor; D008562:Membrane Glycoproteins; D011518:Proto-Oncogene Proteins; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; C081026:CD68 protein, mouse; D000097382:CD68 Molecule